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Pharmacology - MRCPsych A > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

Name some facts about buspirone?

A
  • Causes no dependence
  • Doesn’t have street value
  • Doesn’t cause tolerance
  • Can be withdrawn easily
  • Has to be dose TDS as has a short half life
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2
Q

Quetiapine has a….

A

Short half life (7 hours) compared to Olanzapine/Clozapine/Risperidone

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3
Q

Name some drugs which undergo very little hepatic metabolism and therefore detectable in urine?

A

Gabapentin, Lithium, Amisulpride and Sulpride

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4
Q

Why can Aripiprazole be dosed at OD

A

As it has a long half life of 72 hours

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5
Q

Pethidine + BLANK can cause a fatal serotonin syndrome?

A

MAOI - tranylcypromine or phenelzine

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6
Q

Name some receptors that Clozapine has effects on

A

Anatgonism:
- D1
- D2 –> weak affinity - at clinically effective doses may only occupy 40-50% of striatal D2 receptors. ? reason why low propensity for EPSEs
- D4 –> strong affinity

  • Alpha 1 adrenergic receptors
  • H1
  • 5-HT2a

Agonism:
- M4 –> ? mechanism behind silaorrhoea

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7
Q

If someone is presenting with alcohol withdrawal and has severe liver damage what benzodiazepines may be of choice?

A

Oxazepam or Lorazepam
- both short acting

  • These benzodiazepines (w/ temazepam) do not undergo phase 1 metabolism through cytochrome P450 enzymes and are instead proceed straight to phase 2, are conjugated (glucuronidation) and excreted.
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8
Q

What does a high therapeutic index mean?

A

A drug is very safe in relation to clinical effectiveness

Methods of calculating indices include:
- Medium lethal dose (LD-50) / medium effective dose (ED-50)
- Minimum toxic dose / minimum effective dose

Drugs OTC will have a higher therapeutic index i.e paracetamol

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9
Q

Outline the hepatic enzyme inducers or inhibitors?

A

Inducers:

Carbamazepine
Rifampicin
Alcohol (chronic)
Phenytoin

Gresofulvin
Phenobarbitone
Smoking
St Johns Wart

Topiramate

Inhibitors:

SICK ACES COM GAQ

Sodium Valproate
Isoniazid
Cimetidine
Ketokonazole / Fluconazole

Alcohol (acute)
Chlorphenicol
Erythromycin
Sulfamides

Ciprofloxacin
Omeprazole
Metronidazole

Grapefruit juice
Amiodarone
Quinidine

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10
Q

Broadly name some medications that undergo metabolism by the P450 system?

A

Most anti-depressants / antipsychotics

Benzodiazepines

Warfarin

Zolpidem

Sodium Valproate

Methadone

Thyroxine

Oestrogen

Steroids

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11
Q

Name a reversible MAOI

A

Moclobemide (rMAO-A inhibitor) - reversible MAOIs are preferable given there is less tendency for the cheese reaction

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12
Q

Which anti-depressants have been associated with a therapeutic window

A

Imipramine, Desipramine and Nortrptyline (although dubious benefit of the value of them)

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13
Q

Name some psychotropic drugs that can be given in hepatic impairment?

A

Antipsychotics - Amisulpride and Sulpride - no dosage reduction if renal function is normal. Paliperidone if depot needed

Anti-depressants - Paroxetine, Vortioxetine, Citalopram, Sertraline

Hypnotics - Lorazepam, Oxazepam and Temepezam - these have no active metabollites. Can be used cautiously starting at a low dose as sedatives may trigger hepatic encephalopathy. Zopiclone 3.75mg may be used also.

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14
Q

Why may Zolpidem be a good choice for hypnotic?

A

Peak level at 1.6hrs, half-life 2.6hrs
No active metabolites

These make it short acting therefore if a patient needs to do an activity in the morning and can’t be sedated

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15
Q

When does a drug which does not require a loading dose reach a steady state?

A

4-5 half lives

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16
Q

Name the active metabolites of imipramine and amitriptyline

A

Imipramine - Desipramine

Amitriptyline - Nortryptiline

Both through cytochrome P450 enzymes

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17
Q

Outline the differences between zero order and first order kinetics?

A

1st order kinetics - the rate of drug elimination (per unit of time) is proportion to the concentration of the drug.

Zero-order kinetics - the rate of drug elimination is not

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17
Q

Outline the differences between zero order and first order kinetics?

A

1st order kinetics - the rate of drug elimination (per unit of time) is proportion to the concentration of the drug.

Zero-order kinetics - the rate of drug elimination is not proportional to drug concentration - static rate of elimination. Occurs when elimination is saturated at higher doses. Present for alcohol, high dose salicylates, high dose fluoxetine and high dose omeprazole.

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18
Q

What does clearance depend on?

A

The half-life of a drug

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19
Q

Define clearance

A

The volume of blood cleared of a particular drug in a unit of time.

It represents the relationship between elimination rate and drug concentration.

Rate of clearance determines the half-life of a drug

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20
Q

What is autoinduction?

A

Where a drug induces its own metabolism - this occurs for Carbamazepine therefore it takes 2 weeks for it to reach a steady state

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21
Q

Name an anti-depressant that undergoes autoinhibition?

A

Paroxetine - CYP450 2D6 inhibitor

Increasing the dose by 50% may lead to double plasma concentration

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22
Q

How does Fluoxetine increase the effect of warfarin

A

Through P450 inhibition - increases warfarin levels, also haloperidol, carbamazepine, phenytoin

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23
Q

How does Clonidine work?

A

Through agonism of presynaptic alpha-2 adrenergic receptors.

Decreases sympathetic outflow causing vasodilation and less NAA release from presynaptic nerve terminals - lowers arousal and sympathetic tone

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24
Q

Which SSRIs are most specific for serotonin reputake?

A

Citalopram
Escitalopram

Have less effect on NAA, GABA and H1

25
Q

How does pharmacokinetics differ in the elderly?

A

Reduced rate of absorption
- lower Gastric pH
- less mesenteric blood flow
- less gut motility

Reduced distribution but increased levels with longer half lived
- Reduced plasma protein binding m- less albumin
- Lower BMI with proportionally increased body fat

Reduced metabolism:
- Less liver breakdown from reduction in efficiency of enzymes and less liver blood flow

Reduced excretion:
- Less renal clearance
- Drug effects are prolonged, cumulative with higher risk of toxicity

26
Q

What are the least sedating TCA’s?

A

Lofepramine and Nortryptyline
- Lofepramine safest in elderly as least likely to cause postural hypotension, lowest propensity for cardiac conduction abnormalities

27
Q

How is amphetamine intoxication treated?

A

Urinary acidification - give ammonium chloride every 2-3 hours and the urine is acidified to help clear the amphetamine

28
Q

Name 3 factors that affect absorption of a drug?

A

Form of the drug - enteric coating etc.

Blood flow at the site of absorption

Solubility of the drug - particle size, pH, pKa of the drug (half of the drug in ionised form)

29
Q

Name some factors that reduce the absorption of drugs from the GI tract?

A

Changes to gastric pH

Food - delays gastric emptying

Intestinal motility changes - diarrhoea

Blood flow integrity

Surface area available

Inhibitors of P-glycoprotein (a transporter that pumps drugs out of intestinal wall into gut) - grapefruit juice is an inhibitor - can increase absorption of benzodiazepines/carbamazepine, calcium channel blockers etc

Dissolution and disintegration of drugs - takes longer for those with enteric coating/wax mixed in - slow release forms take longer to peak therefore less side effects

Gut flora - some have enzymes that aid metabolism of drugs

30
Q

Name some factors that affect distribution

A

Haemodynamic factors - cardiac output

Lipid solubility - permeability factors

Plasma protein binding

Blood-brain barrier

Blood-CSF barrier

31
Q

Name a condition where protein binding reactions may be important?

A

Renal disease - proteinuria

There may be less albumin or apha-1 acid glycoprotein therefore free fraction could increase

32
Q

Name the properties a particle needs to have to cross the BBB

A
  • Unionised
  • High lipophilic - water coefficient

However those with a low lipid-water coefficient may still be able to cross through carrier transporters (Valproate or L-DOPA) or through cerebral circulation e.g. Lithium Ions

33
Q

Subfornical organ, area postrema of the medulla and median eminence make up the…

A

Circumventricular organs - no BBB - useful to detect toxic substances easily so can initiate vomiting etc

34
Q

What is bioequivalence?

A

The degree of comparability between two formulations of the same drug

Need to have same bioavailability and rate of absorption

35
Q

Name the four major metabollic reactions

A

Oxidation, reduction, hydrolysis and conjugation

36
Q

What are the two routes of metabolism

A

Phase 1: oxidation, reduction, hydrolysis - generally done by CYP450 enzymes. Active/inactive metabolite then ready for conjugation

Phase 2: conjugation by adding glucuronic acid. Makes a more polar - water soluble ready for excretion in bile or urine dependent on relative molecular mass. If mass < 300 in urine.

37
Q

Name two CYP450 enzymes that psychotropics are typically broken down by?

A

CYP2D6 - can be inhibited by fluoxetine, amitriptyline, clomipramine & neuroleptics -drugs metabolised:
- All TCAs
- fluoxetine, paroxetine
- trazodone, nefazodone
- valproate, all neuroleptics, risperidone

CYP3A4 (in gut wall) - barbiturates and carbamazepine inducer, fluoxetine can inhibit:
- Clomipramine
- Fluvoxamine,
- Mirtazapine,
- Nefazodone,
- Carbamazepine
- most benzodiazepines

38
Q

How do Fluxoetine and Fluvoxamine affect metabolism of psychotropics?

A

Inhibitor CYP450 enzymes (2D6 and 2C19) and can increase levels

  • Fluvoxamine may increase level of Clozapine 10 fold
39
Q

How do smoking and caffeine affect the metabolism of some psychotropic drugs?

A

Influence glucuronidation reaction via CYP1A2 or UGT enzyme

Caffeine inhibits CYP1A2 - increases levels of Clozapine and Olanzapine

Smoking induces CYP1A2 - lowers levels

40
Q

What drug forms are suitable for renal excretion?

A

Ionised and non-lipid soluble

41
Q

What factors affect renal excretion?

A
  • Age
  • Blood flow to kidneys
  • Renal impairment
  • pH in the urine
42
Q

Name some drugs that undergo almost all renal excretion without any hepatic breakdown

A

Lithium, Sulpride, Amisulpride, Gabapentin, Acamprosate, Amantadine

43
Q

What is distribution half-life?

A

Time taken from initial peak (Cmax) to half i.e. the time that redistribution halves the initial peak

44
Q

What is elimination half life?

A

The time taken for elimination to halve the plasma concentration - most relevant for clinicians

45
Q

indexWhen is a steady state of a drug achieved?

A

When 4-5 half lives have been administered

Steady state is rate in = rate out

46
Q

Name some drugs with a narrow therapeutic index range?

A

Lithium, Carbamazepine, Phenytoin

47
Q

How does therapeutic window and therapeutic index range differ?

A

Therapeutic window - only concerns therapeutic range i.e. above does not consider toxicity

Therapeutic index range - considers effect and safety/toxicity

48
Q

Name some careful prescribing tips for Renal impairment

A

Benzodiazepines with caution:
- Diazepam metabolite can accumulate
- Half life of Lorazepam increased from 8-25 to 32-72. If impairment consider halving dose

Antipsychotics
- Avoid Lithium/Amisulpride (later all renally excreted)
- Haloperidol ok unless causing SE - monitor for sedation/postural hypotension
- Risperidone metabolite can accumulate

Anti-D:
- Sertraline avoided
- Amitriptilyine and Imipramine - no dose reduction needed
- Dose reductions for Citalopram and Paroxetine
- Fluoxetine and Fluvoxamine ok

49
Q

How protein bound are TCAs?

A

Extensively bound - imipramine 80-95%

50
Q

After 5 half lives how much of a drug is in a steady state?

A

97%

After 7 half lives 99% of a drug is in a steady state

51
Q

A patient’s clozapine level + 1mg/L wyd?

A

Reduce dose +/- prescribe anticonvulsant coverage (not bone marrow due as its an enzyme inducer and can also suppress bone marrow)

52
Q

A patient’s clozapine level + 1mg/L wyd?

A

Likely reduce dose +/- prescribe anticonvulsant coverage (not bone marrow due as its an enzyme inducer and can also suppress bone marrow)

> 2mg/L definitely reduce the dose and prescribe an anticonvulsant

53
Q

Which clozapine complication is dose related?

A

Seizures - the other are idiosyncratic or allergic in nature

54
Q

What is the optimum clozapine dose?

A

0.35-0.6 mg/L

55
Q

Why may clozapine:norclozapine ratio be helpful?

A

Can indicate non-compliance

Should be 1.33:1 (or 0.66:1 if norclozapine:clozapine)

If clozapine:norclozapine is < 1 could indicate non-compliance - to be interpreted with caution given genetic factors, incorrect sampling time and the influence of other drugs e.g. fluovaxmine - inhibitor

56
Q

Name some drugs that may cause Lithium levels to increase due to poor renal excretion?

A

NSAIDs

Thiazide like diuretics (not loop/K+ sparing)

ACEi

Angiotensin-II-blockers

Note hyponatraemia can also elevate lithium levels through increased reabsorption at renal tubule

57
Q

Name some drugs which Carbamazepine reduces the concentration of?

A

Clozapine, risperidone, amitriptyline - through CYP1A2, CYP2C19, CYP3A enzyme induction

Carbamazepine takes 2-3 weeks to reach a steady state
Therapeutic drug window 4-10mg/L

58
Q

What drugs may increase levels of Carbamazepine

A

Clarithromycin, Fluconazole and Diltiazem

59
Q

Why should combination of anti-D fluoxetine/paroxetine + TCA matter?

A

Fluoxetine/Paroxetine are inhibitors of CYP450 system therefore the dose of TCAs will go up increasing risk of serotonin syndrome

60
Q

If augmenting Clozapine what plasma concentration should be aimed for?

A

< 1mg/L

Pharmacology - MRCPsych A (5 decks)

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